Human Molecular Genetics Advance Access published online on December 12, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn426
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Delivery of recombinant follistatin lessens disease severity in a mouse model of Spinal Muscular Atrophy
1 Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, Missouri 2 Department of Veterinary Pathobiology, University of Missouri, Columbia, Missouri
* Corresponding author Christian L. Lorson, Ph.D. Department of Veterinary Pathobiology Life Sciences Center, Room 471G University of Missouri Columbia, MO 65211 USA Phone: 573 884-2219 Fax: 573 884-9395 Email: lorsonc{at}missouri.edu
Received August 22, 2008; Revised November 18, 2008; Accepted December 10, 2008
Spinal Muscular Atrophy (SMA) is the most common genetic cause of infant mortality. SMA is caused by loss of functional Survival Motor Neuron 1 (SMN1), resulting in death of spinal motor neurons. Current therapeutic research focuses upon modulating the expression of a partially functioning copy gene, SMN2, which is retained in SMA patients. However, a treatment strategy that improves the SMA phenotype by slowing or reversing the skeletal muscle atrophy may also be beneficial. Myostatin, a member of the TGF-β super-family, is a potent negative regulator of skeletal muscle mass. Follistatin is a natural antagonist of myostatin and over-expression of follistatin in mouse muscle leads to profound increases in skeletal muscle mass. To determine whether enhanced muscle mass impacts SMA, we administered recombinant follistatin to a SMA mouse model. Treated animals exhibited increased mass in several muscle groups, elevation in the number and cross-sectional area of ventral horn cells, gross motor function improvement, and mean lifespan extension by 30%, by preventing some of the early deaths, as compared to control animals. SMN protein levels in spinal cord and muscle were unchanged in follistatin-treated SMA mice, suggesting that follistatin exerts its effect in an SMN-independent manner. Reversing muscle atrophy associated with SMA may represent an unexploited therapeutic target for the treatment of SMA.
These authors contributed equally to this work
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